Research: A fundamental mechanism in the pathogenesis of animal and human prion diseases is the conformational conversion of a normal host-encoded protein (PrPc) from a non-infectious, soluble, protease sensitive form to an infectious, aggregated, protease resistant, pathologic form termed PrPSc. The precise mechanism of prion conversion is not known and it is unknown if accessory molecules, in addition to prion protein, aid in the conversion process. However, there are data that do support the requirement for an accessory molecule. The goal of this project is to use a comparative transcriptomics approach on scrapie permissive sheep cell lines to identify possible accessory proteins necessary for PrP accumulation. The hypothesis to be tested is that PrPSc accumulation requires an accessory protein(s). Specific Aim 1 will determine if in vivo PrPSc permissive sheep cells maintain permissiveness in stable cell cultures. Specific Aim 2 will determine if unique gene expression patterns in permissive cells can be associated with PrPSc accumulation. Specific Aim 3 will determine if expression of a PrPSc-accumulation-associated gene(s) is required for PrPSc accumulation. The findings of the proposed study have applications to both human and veterinary medicine by defining the genetic response to prion accumulation and identifying co-factors required for the accumulation of PrPSc. Such co-factors would be putative targets for therapeutic intervention or potential surrogate markers for antemortem diagnosis. Candidate: The candidate is a veterinarian completing a residency in anatomic pathology and a Ph.D. degree. After fulfilling most of the requirements of his pathology training along with all didactic course work and his candidacy exam, the candidate is actively pursuing the research portion of his training. This research proposal constitutes his plan to investigate mechanisms of prion replication. Long-term goals of the candidate include investigation of infectious diseases of animals with zoonotic potential. Environment: The Department of Veterinary Microbiology and Pathology at Washington State University provides both modern research facilities for infectious disease research and a highly interactive training environment including intra- and interdisciplinary graduate education, residency programs, and extensive collaboration both within and outside the university. The sponsor collaborates closely in research and has successfully mentored graduate students to research independence.